Medicine and Health Sciences Commons^™

A Single Vertebrate Dna Virus Protein Disarms Invertebrate Immunity To Rna Virus Infection, Don B. Gammon, Sophie Duraffour, Daniel K. Rozelle, Heidi Hehnly, Rita Sharma, Michael E. Sparks, Cara C. West, Ying Chen, James J. Moresco, Graciela Andrei, John H. Connor, Darryl Conte Jr., Dawn E. Gundersen-Rindal, William L. Marshall, John R. Yates, Neal S. Silverman, Craig C. Mello

Neal Silverman

Virus-host interactions drive a remarkable diversity of immune responses and countermeasures. We found that two RNA viruses with broad host ranges, vesicular stomatitis virus (VSV) and Sindbis virus (SINV), are completely restricted in their replication after entry into Lepidopteran cells. This restriction is overcome when cells are co-infected with vaccinia virus (VACV), a vertebrate DNA virus. Using RNAi screening, we show that Lepidopteran RNAi, Nuclear Factor-kappaB, and ubiquitin-proteasome pathways restrict RNA virus infection. Surprisingly, a highly conserved, uncharacterized VACV protein, A51R, can partially overcome this virus restriction. We show that A51R is also critical for VACV replication in vertebrate cells …

Bacterial Rna:Dna Hybrids Are Activators Of The Nlrp3 Inflammasome, Sivapriya Kailasan Vanaja, Vijay A. K. Rathinam, Maninjay K. Atianand, Parisa Kalantari, Brian M. Skehan, Katherine A. Fitzgerald, John M. Leong

Katherine A. Fitzgerald

Enterohemorrhagic Escherichia coli (EHEC) is an extracellular pathogen that causes hemorrhagic colitis and hemolytic uremic syndrome. The proinflammatory cytokine, interleukin-1beta, has been linked to hemolytic uremic syndrome. Here we identify the nucleotide-binding domain and leucine rich repeat containing family, pyrin domain containing 3 (NLRP3) inflammasome as an essential mediator of EHEC-induced IL-1beta. Whereas EHEC-specific virulence factors were dispensable for NLRP3 activation, bacterial nucleic acids such as RNA:DNA hybrids and RNA gained cytosolic access and mediated inflammasome-dependent responses. Consistent with a direct role for RNA:DNA hybrids in inflammasome activation, delivery of synthetic EHEC RNA:DNA hybrids into the cytosol triggered NLRP3-dependent responses, …

Dual Engagement Of The Nlrp3 And Aim2 Inflammasomes By Plasmodium-Derived Hemozoin And Dna During Malaria, Parisa Kalantari, Rosane B. Deoliveira, Jennie Chan, Yolanda Corbett, Vijay A. K. Rathinam, Andrea Stutz, Eicke Latz, Ricardo T. Gazzinelli, Douglas T. Golenbock, Katherine A. Fitzgerald

Katherine A. Fitzgerald

Hemozoin (Hz) is the crystalline detoxification product of hemoglobin in Plasmodium-infected erythrocytes. We previously proposed that Hz can carry plasmodial DNA into a subcellular compartment that is accessible to Toll-like receptor 9 (TLR9), inducing an inflammatory signal. Hz also activates the NLRP3 inflammasome in primed cells. We found that Hz appears to colocalize with DNA in infected erythrocytes, even before RBC rupture or phagolysosomal digestion. Using synthetic Hz coated in vitro with plasmodial genomic DNA (gDNA) or CpG oligodeoxynucleotides, we observed that DNA-complexed Hz induced TLR9 translocation, providing a priming and an activation signal for inflammasomes. After phagocytosis, Hz and …

Malaria-Induced Nlrp12/Nlrp3-Dependent Caspase-1 Activation Mediates Inflammation And Hypersensitivity To Bacterial Superinfection, Marco A. Ataide, Warrison A. Andrade, Dario S. Zamboni, Donghai Wang, Maria Do Carmo Souza, Bernardo S. Franklin, Samir Elian, Flaviano S. Martins, Dhelio Pereira, George W. Reed, Katherine A. Fitzgerald, Douglas T. Golenbock, Ricardo T. Gazzinelli

Katherine A. Fitzgerald

Cyclic paroxysm and high fever are hallmarks of malaria and are associated with high levels of pyrogenic cytokines, including IL-1beta. In this report, we describe a signature for the expression of inflammasome-related genes and caspase-1 activation in malaria. Indeed, when we infected mice, Plasmodium infection was sufficient to promote MyD88-mediated caspase-1 activation, dependent on IFN-gamma-priming and the expression of inflammasome components ASC, P2X7R, NLRP3 and/or NLRP12. Pro-IL-1beta expression required a second stimulation with LPS and was also dependent on IFN-gamma-priming and functional TNFR1. As a consequence of Plasmodium-induced caspase-1 activation, mice produced extremely high levels of IL-1beta upon a second …

Increased Risk For Vitamin D Deficiency In Obese Children With Both Celiac Disease And Type 1 Diabetes, Nithya Setty-Shah, Louise S. Maranda, Benjamin U. Nwosu

Benjamin U. Nwosu

Background. It is unknown whether the coexistence of type 1 diabetes (T1D) and celiac disease (CD) increases the risk for vitamin D deficiency.

Aims. To determine the vitamin D status and the risk for vitamin D deficiency in prepubertal children with both T1D and CD compared to controls, TID, and CD.

Subjects and Methods. Characteristics of 62 prepubertal children of age 2–13 y with either CD + T1D (� = 22, 9.9 ± 3.1 y), CD only (� = 18, 8.9 ± 3.3 y), or T1D only (� = 22, 10.1 ± 2.8 y) were compared to 49 controls of …

The Fit-Hansa Demonstrates Reliability And Convergent Validity Of Functional Performance In Patients With Shoulder Disorders, Prajyot Kumta, Joy Macdermid, Saurabh Mehta, Paul Stratford

Saurabh Mehta

Study

DesignPsychometric study design.

Objectives

To assess the test-retest reliability and convergent validity of the Functional Impairment Test-Hand and Neck/Shoulder/Arm (FIT-HaNSA) in patients with shoulder disorders.

Background

Performance tests that assess functional ability of patients with shoulder disorders can provide useful information for making clinical or return-to-activity decisions. No performance-based shoulder test has yet demonstrated sufficient relevance or clinical measurement properties. The FIT-HaNSA examines upper extremity performance during repetitive tasks that emphasize shoulder reaching and static postures and, therefore, has greater relevance for assessing performance.

Methods

Thirty-six patients with shoulder disorders and 65 healthy controls were recruited for the study. …

The Implications Of Chronic Pain Models For Rehabilitation Of Distal Radius Fracture, Saurabh Mehta, Joy Macdermid, Mary Tremblay

Saurabh Mehta

Distal radius fracture (DRF) is the most common fracture and usually occurs as a result of a fall. Most patients recover following DRF with minimal residual pain or disability; however, a small subset of patients continue to experience pain and disability even one year after the injury. Currently, there are no practice guidelines for early identification and treatment of patients who are potentially at greater risk of developing these adverse outcomes. As a result, hand therapy management of patients following DRF does not incorporate screening of these at-risk patients. The objective of this paper is to apply constructs from learned …

Development Of A Self-Report Measure Of Dual Diagnosis Capability For Addiction And Mental Health Programs, Kenneth E. Fletcher, Anna Kline, Tara Zandi, Gregory Seward, Sun Kim, Douglas M. Ziedonis

Douglas M. Ziedonis

The purpose of this study is to develop and test the psychometrics of a self-report version of a measure of the capacity of addiction and mental health programs to deliver dual-diagnosis treatment, that is, to provide treatment for both addiction problems and mental health problems. Traditionally these services are provided by very different service providers that did not until recently interact very well, if at all. The increasing recognition that patients who suffer from both kinds of problems – who are dually diagnosed – would benefit from integrated delivery of addiction and mental health services has led to efforts to …

Implementing The Massachusetts Child Trauma Project (Mctp) To Improve Services For Children With Complex Trauma In Child Welfare: Phase I Needs And Readiness Assessment, Charmaine B. Lo, Melodie Wenz-Gross, Jessica L. Griffin

Melodie Wenz-Gross

MCTP seeks to improve placement stability and outcomes for children with complex trauma in the care of the Massachusetts Department of Children and Families (DCF) by creating a sustainable capacity for providing evidence-based trauma interventions within provider agencies, and trauma-informed practices within DCF.

Outpatient Commitment: A Competency Based Justification, Albert J. Grudzinskas, Jeffrey L. Geller, Jonathan C. Clayfield, William H. Fisher

Jeffrey L. Geller

A recent survey of state statutes for outpatient commitment (Torrey and Kaplan, 1995) indicates that while thirty-five states and the District of Columbia have laws permitting outpatient commitment, Massachusetts is not one of them. Rather, Massachusetts uses a competency-based, substituted-decision-making model for the involuntary administration of medication in the community. To appreciate the Massachusetts model, it is important to understand how this court-ordered involuntary outpatient treatment fits into the overall scheme of outpatient commitment and how it is structured. A review of involuntary outpatient treatment (IOT) literature indicates that it is prudent to distinguish between outpatient commitment, conditional release, and …

The Family Options Project: Implementing An Innovative Intervention For Parents With Mental Illnesses And Their Families, Joanne Nicholson, Kathleen Biebel, Valerie F. Williams, Elizabeth A. Aaker, Karen Albert, Bernice Gershenson, Brenda Warren, Katherine Woolsey

Kathleen Biebel

The Family Options Project reflects a productive partnership between researchers and providers at the UMMS Center for Mental Health Services Research and Employment Options, Inc., Marlborough, MA The Family Options Intervention is an evidence-informed psychiatric rehabilitation intervention, developed and tested within the context of a community-based agency setting.

Use Of Sildenafil To Facilitate Weaning From Inhaled Nitric Oxide In Children With Pulmonary Hypertension Following Surgery For Congenital Heart Disease, Jaclyn E. Lee, Simon C. Hillier, Chad A. Knoderer

Chad A. Knoderer

Pulmonary hypertension frequently complicates the postoperative management of patients after congenital cardiac surgery. Inhaled nitric oxide is an effective treatment option, but rebound pulmonary hypertension can occur upon its withdrawal. Sildenafil may facilitate its withdrawal by restoring cyclic guanosine monophosphate availability via phosphodiesterase-5 inhibition. The purpose of this study was to evaluate the use of sildenafil in facilitating weaning from inhaled nitric oxide after congenital cardiac surgery in patients who had previously failed weaning, and to compare the effects of sildenafil on pulmonary and systemic hemodynamics. Children who received sildenafil after cardiovascular surgery during a 23-month period at Riley Hospital …

Linezolid-Associated Thrombocytopenia In Children With Renal Impairment, Chad A. Knoderer, Kristen R. Nichols, Heather L. Deyoung, Sara J. Jones, Elaine G. Cox

Chad A. Knoderer

Poster presented at ID Week, October 2013, San Francisco, California.

Assessment Of The Validity Of Reported Antibiotic Allergic Reactions In Pediatric Patients, Lauren Miller, Chad Knoderer, Elaine Cox, Martin Kleinman

Chad A. Knoderer

Study Objective. To determine whether a reported antibiotic allergy was likely to have been immunologically mediated. Design. Questionnaire-based study. Setting. Tertiary care, freestanding children's hospital. Patients. One hundred patients aged 1 month-18 years for whom guardians reported an allergy to an antibiotic at the time of hospital admission between October 2009 and March 2010. Intervention. Guardians of the patients were interviewed by using a standardized allergy assessment questionnaire. Measurements and Main Results. Based on answers to the questionnaire, the reported allergic reactions were categorized to determine if they were true allergies or adverse reactions. Among the 100 patients, reported allergies …

Outcomes Of Extended-Infusion Piperacillin/Tazobactam In Pediatric Patients., Kristen Nichols, Katie Andricopulos, Ashley Crumby, Elaine Cox, Chad Knoderer

Chad A. Knoderer

Poster presented at: ID Week 2013, October 2013, San Francisco, California.

Nonsteroidal Anti-Inflammatory Drugs Are An Important Cause Of Acute Kidney Injury In Children, Jason Misurac, Chad Knoderer, Jeffrey Leiser, Corina Nilescu, Amy Wilson, Sharon Andreoli

Chad A. Knoderer

Objective To characterize nonsteroidal anti-inflammatory drug (NSAID)-associated acute kidney injury (AKI) in children. Study design We conducted a retrospective chart review of children diagnosed with AKI through the use of International Classification of Diseases, Ninth Revision diagnosis code 584.5 or 584.9 from January 1999 to June 2010. Medical records were reviewed to confirm the diagnosis of AKI and to quantify NSAID administration. Pediatric RIFLE criteria were used to codify AKI. Patients were not classified as having NSAID-associated AKI if they had a diagnosis explaining AKI or comorbid clinical conditions predisposing to AKI development. Results Patients (N = 1015) were identified …

A Randomized, Controlled Trial Of Catheter-Related Infectious Event Rates Using Antibiotic-Impregnated Catheters Versus Conventional Catheters In Pediatric Cardiovascular Surgery Patients, Elaine G. Cox, Chad A. Knoderer, Aimee Jennings, John W. Brown, Mark D. Rodefeld, Scott G. Walker, Mark W. Turrentine

Chad A. Knoderer

We conducted a randomized, controlled clinical trial to determine whether a difference in catheter-associated blood stream infection (CABSI) incidence existed between children who underwent cardiac surgery and had a central venous catheter impregnated with minocycline and rifampin versus those who had a conventional, nonimpregnated catheter after cardiac surgery. Due to a lower number of infections than expected, the study was terminated early. Among 288 evaluable patients, the rates of CABSI and line-related complications were similar between the 2 groups.

Sildenafil For The Treatment Of Pulmonary Hypertension In Pediatric Patients, Alice Huddleston, Chad Knoderer, Jennifer Morris, Eric Ebenroth

Chad A. Knoderer

Sildenafil is a phosphodiesterase 5 inhibitor widely used for the treatment of pulmonary hypertension in children. Despite limited available safety and efficacy evidence, use of sildenafil continues to increase. To date, sildenafil use for pediatric pulmonary hypertension has been characterized for 193 children through 16 studies and 28 case series and reports. The primary efficacy data suggest that sildenafil is beneficial for facilitating the weaning of inhaled nitric oxide in children after cardiac surgery. Compiled safety data suggest that sildenafil is well tolerated among children with idiopathic pulmonary arterial hypertension and pulmonary arterial hypertension associated with congenital heart disease. This …

Cefuroxime Pharmacokinetics In Pediatric Cardiovascular Surgery Patients Undergoing Cardiopulmonary Bypass, Chad A. Knoderer, Sarah A. Saft, Scott G. Walker, Markl D. Rodefeld, Mark W. Turrentine, John W. Brown, Daniel P. Healy, Kevin M. Sowinski

Chad A. Knoderer

Objectives The objective of this study was to determine the pharmacokinetics of cefuroxime in children undergoing cardiopulmonary bypass (CPB) for cardiovascular surgery. Design A prospective study. Setting A tertiary pediatric teaching hospital. Participants Infants and children undergoing CPB were enrolled in the study. Intervention An initial dose (mean, 24.2 ± 1.6 mg/kg) of cefuroxime was administered before surgical incision, and a second dose (mean, 14.4 ± 7.9 mg/kg) was administered in the CPB prime solution. Serial blood samples were obtained before, during, and after the CPB process. Samples were shipped on dry ice to the analytic laboratory and concentrations determined …

Impact Of Decmedetomidine On Opioid And Benzodiazepine Dosing Requirements In Children., Amy E. Helvie, Chad A. Knoderer, Iftekhar D. Kalsekar, Brandon T. Kibby, Michael S. Mazurek

Chad A. Knoderer

Poster presented at: Annual Update on Pediatric Cardiovascular Disease; February 2008; Scottsdale Arizona.

Pharmacokinetics Of Cefuroxime Are Not Significantly Altered By Cardiopulmonary Bypass In Children, Chad Knoderer, Sarah Saft, Scott Walker, Daniel Healy, Kevin Sowinski

Chad A. Knoderer

Poster presented at: SPA/AAP PEDIATRIC ANESTHESIOLOGY 2010 - Winter Meeting; April 2010; San Antonio, TX.

Efficacy Of Limited Cefuroxime Prophylaxis In Pediatric Patients After Cardiovascular Surgery, Chad Knoderer, Elaine Cox, Michelle Berg, Andrea Webster, Mark Turrentine

Chad A. Knoderer

Purpose The efficacy of limited cefuroxime prophylaxis in pediatric patients after cardiovascular surgery was evaluated. Methods All patients age 18 years or younger who underwent cardiovascular surgery and received postoperative care from the cardiovascular surgery team between February and July 2006 (preintervention group) and between August 2006 and January 2007 (postintervention group) were eligible for study inclusion. Patients were excluded if they did not receive cefuroxime as postoperative prophylaxis, had a preexisting infection, underwent cardiac transplantation or extracorporeal membrane oxygenation, or underwent delayed sternal closure. The preintervention group received prolonged cefuroxime prophylaxis, and the postintervention group received 24 hours of …

Clinical Issues Surrounding Once-Daily Aminoglycoside Dosing In Children, Chad A. Knoderer, Julie A. Everett, William F. Buss

Chad A. Knoderer

Aminoglycoside antibiotics are first-line treatment for many infectious diseases in the pediatric population and are effective in adults. The traditional dosing interval in children is every 8–12 hours. Studies in adults reported equivalent efficacy and equal or less toxicity with once-daily regimens. Despite many studies in the adult population, this approach has yet to become standard practice in most pediatric hospitals. Reasons for lack of acceptance of this strategy in children include rapid aminoglycoside clearance, unknown duration of postantibiotic effect, safety concerns, and limited clinical and efficacy data.

Chronic Outpatient Sildenafil Therapy For Pulmonary Hypertension In A Child After Cardiac Surgery, Chad A. Knoderer, E. S. Ebenroth, J. W. Brown

Chad A. Knoderer

We report the case of a 14-month-old male with d-transposition of the great arteries, ventricular septal defect, and pulmonary hypertension successfully treated with long-term sildenafil following cardiac surgery. To our knowledge, this is the first published report of long-term sildenafil treatment in a child after corrective cardiac surgery.

Survey Of Congenital Heart Surgeons’ Preferences For Antimicrobial Prophylaxis For Pediatric Cardiac Surgery Patients, Chad A. Knoderer, Emily M. Anderson, Elaine G. Cox

Chad A. Knoderer

Patients with congenital heart defects are a unique population with generally immature immune systems. Fragility in the postoperative period may contribute to surgical site infections (SSIs), a life threatening complication for this population. The need for postoperative antimicrobial prophylaxis for these patients is a standard of care that is indisputable. When choosing an antimicrobial regimen for surgical prophylaxis, consideration should be given to balancing the prevention of nosocomial infections, avoiding emergence of bacterial resistance, and minimizing drug toxicities and cost.

Fenoldapam For Acute Kidney Injury In Children, Chad A. Knoderer, Jeffrey D. Leiser, Corina Nailescu, Mark W. Turrentine, Sharon P. Andreoli

Chad A. Knoderer

We report two cases of children with severe cardiomyopathy requiring treatment with ventricular assist devices who developed acute kidney injury and were treated with fenoldopam. Therapy with fenoldopam appeared successful in one case in that renal replacement therapy was avoided with improvement in urine output and renal function. These are the first reported cases of fenoldopam use in children with acute kidney injury receiving mechanical circulatory support.

Attitudes Of Women In Their Forties Toward The 2009 Uspstf Mammogram Guidelines: A Randomized Trial On The Effects Of Media Exposure, Autumn Davidson, Xun Liao, B. Magee

B. Dale Magee

OBJECTIVE: The objective of the study was to assess women's attitudes toward 2009 US Preventive Services Task Force mammography screening guideline changes and evaluate the role of media in shaping opinions. STUDY DESIGN: Two hundred forty-nine women, aged 39-49 years, presenting for annual examinations randomized to read 1 of 2 articles, and survey completion comprised the design of the study. RESULTS: Eighty-eight percent overestimated the lifetime breast cancer (BrCa) risk. Eighty-nine percent want yearly mammograms in their 40s. Eighty-six percent felt the changes were unsafe, and even if the changes were doctor recommended, 84% would not delay screening until age …

Role Of Multiple Births In Very Low Birth Weight And Infant Mortality, B. Magee

B. Dale Magee

OBJECTIVE: To determine the percentage of very-low-birth-weight (VLBW) infants (g) and infant deaths attributable to multiple births in the general population and in women aged 35+. STUDY DESIGN: The year 2000 Massachusetts birth certificate database with linked births-deaths was examined. Etiologic fractions (EF) for VLBW and infant mortality attributable to multiples were calculated for the general population and the 35+ age group. The percentages of multiples occurring in the 35+ age group were calculated. Infant deaths due to congenital anomalies and "perinatal conditions" were calculated. RESULTS: There were 81,582 resident births in Massachusetts in 2000. Of them 4.3% were multiples. …

Xk Aprosencephaly And Anencephaly In Sibs, Phillip Townes, Karen Reuter, E. Rosquete, B. Magee

B. Dale Magee

Recent studies have suggested a causal and pathogenetic relationship between holoprosencephaly and anencephaly. In support of the proposed relationship we report a sibship that includes anencephalic male twins and a female infant with a severe form of alobar holoprosencephaly, radial aplasia, and oligodactyly. The upper limb and brain malformations are considered to represent aprosencephaly syndrome. The coexistence of anencephaly and aprosencephaly within a sibship suggests that XK aprosencephaly syndrome may be an autosomal recessive disorder.

Missed Opportunities In Hpv Vaccination, B. Dale Magee, Autumn S. Davidson, Leslie Regh

B. Dale Magee

Objective: To use the 3 dose Human Papillomavirus (HPV) vaccine administration (given at 0, 1-2 and 6 months) to quantify opportunities to improve efficacy in the delivery of preventive health services. Methods: This was a retrospective, claims-based analysis using data provided by a single managed care plan. Female patients aged 9-26 who were continuously enrolled between 2009 through 2011 and received ≥ dose of the HPV vaccine during 2010 were analyzed. The proportion of initiators who did and did not completed the vaccine series, the timing and location of doses, and the number of outpatient visits during which the vaccine …